This application is concerned with the use of a combination of cocoa procyanidins and aspirin as an anti-platelet therapy.
A compound consisting of one aromatic ring which contains at least one hydroxyl group is classified as a simple phenol. A polyphenol therefore consists of more than one aromatic ring, each ring containing at least one hydroxyl group. Flavonoids are polyphenols which have a diphenyl propane (C6-C3-C6) skeleton structure, and are found ubiquitously in the plant kingdom. The class of flavonoids called the proanthocyanidins are oligomers of flavan-3-ol monomer units most frequently linked 4xe2x86x926 or 4xe2x86x928. One of the most common classes of proanthocyanidins are the procyanidins, which are oligomers of catechin and epicatechin, and their gallic acid esters.
It is known that regular consumption of dietary polyphenols, commonly found in a variety of fruits and vegetables, contributes to a reduction in mortality from cardiovascular disease (CVD), including stroke, heart disease and vascular thrombosis. Red wine, green tea and cocoa have all been identified as being rich in polyphenols, and red wine and green tea have both been shown to be inversely associated with heart disease deaths in industrialized countries.
In addition to reducing the risk of atherogenesis, dietary polyphenols have been shown to have a variety of other potentially beneficial biological activities. For example, they have been shown to inhibit viral reverse transcriptase, inhibit the replication of HIV I in vitro, suppress ulcer formation, and are antimutagenic, neuroprotective, anti-inflammatory, anti-bacterial, hypotensive, and cytotoxic to a variety of cancer cell types.
The mechanisms by which the dietary polyphenols exert their biological functions are not fully understood, but it is known that they have powerful anti-oxidant properties and have an inhibitory effect on platelet activity.
Aspirin (acetylsalicylic acid) is the prototype non-steroidal anti-inflammatory agent. It has been used for many years as an antiplatelet therapy to reduce the risk of recurrent transient ischemic attacks or cerebrovascular accident. The mechanism of action of aspirin is well-defined (Vane, J., Nature, 1971). Put simply, it inhibits the arachidonic acid pathway by causing the alteration of platelet prostaglandin G/H synthase 1, causing the irreversible loss of its cyclooxygenase activity. This results in a decreased conversion of arachidonic acid to the prostaglandins, which are extremely potent mediators of a diverse group of physiological processes. It is the reduced formation of these prostaglandins, in particular thromboxane A2 and prostaglandin E2, which accounts for the variety of pharmacological effects of aspirin that form the basis for its therapeutic use. Unfortunately, the same factors account for the well-documented toxicity of aspirin.
Platelets lack the means with which to synthesize new proteins, which means that the defect caused by aspirin cannot be repaired during the life-span of the platelet. This means that the inhibitory effect of repeated daily doses of aspirin is cumulative, and eventually results in almost complete suppression of platelet thromboxane biosynthesis after 7-10 days. Biochemical, pharmacologic and clinical data support the theory that it is the suppression of thromboxane, leading to a prevention of thromboxane-dependent platelet activation, which accounts for the antithrombotic effects of aspirin.
However, various other prostaglandins produced by the arachidonic acid pathway are responsible for several important homeostatic mechanisms, such as gastric acid secretion, primary hemostasis, control of blood-pressure and renal function. Consequently, long-term aspirin treatment leads to deleterious effects. These include serious gastrointestinal complications, including bleeding and perforation, bleeding complications such as hemorrhagic events, and an increase in the risk of chronic renal disease.
Over the years, an increased understanding of the positive and negative aspects of long-term aspirin treatment has resulted in a downward trend in recommended daily dose, sometimes in combination with low-intensity oral anti-coagulants (in high-risk patients).
Clearly, the discovery of an anti-platelet agent which does not cause the dangerous side-effects of aspirin, and which could either be used to replace aspirin in long-term prevention/treatment regimes, or could be used in tandem with very low doses of aspirin, would be a huge step forward in the treatment and prevention of any disease or disorder caused by platelet dysfunction. Such a discovery would be greeted with great enthusiasm by the medical profession and by members of the public who are either at risk of such disorders or wish to prevent the possibility of such disease occurrence.
The procyanidins present in cocoa have been shown to have an anti-platelet effect both in vitro and in vivo. It has also been shown that the mechanism of the anti-platelet action is not via inhibition of the arachidonic acid pathway. Additionally, it would appear that treatment with low doses of aspirin in combination with cocoa procyanidins results in an enhanced anti-platelet effect, exceeding the anti-platelet effects of the two individual treatments. Therefore, the invention provides an alternative long-term anti-platelet therapy without the unpleasant and dangerous side-effects associated with aspirin.